Clinical Pharmacology Program Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Br J Clin Pharmacol. 2011 Aug;72(2):294-305. doi: 10.1111/j.1365-2125.2011.03963.x.
Sorafenib is a multikinase inhibitor with activity against B-raf, C-raf, VEGFR2, PDGFRβ and FGFR1. Sorafenib is clinically approved for the treatment of renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). The pharmacokinetics (PK) of sorafenib are highly variable between subjects. Sorafenib exposure increases less than dose proportionally (likely due to limited solubility). Sorafenib undergoes enterohepatic recycling (EHC).
This is the first study to characterize the PK of sorafenib using a model based on sorafenib's known disposition characteristics such as delayed/solubility-limited GI absorption and EHC. The parameterization of the EHC model used a square wave function to describe the gall bladder emptying. This study evaluated the effect of baseline bodyweight, BSA, age, gender, liver function parameters, kidney function parameters and genotype with respect to CYP3A41B, CYP3A53C, UGT1A93 and UGT1A95 on sorafenib PK. No clinically important covariates were identified. This model can be used to simulate and explore alternative dosing regimens and to develop exposure-response relationships for sorafenib.
To characterize the pharmacokinetics (PK) of sorafenib in patients with solid tumours and to evaluate the possible effects of demographic, clinical and pharmacogenetic (CYP3A41B, CYP3A53C, UGT1A93 and UGT1A95) covariates on the disposition of sorafenib.
PK were assessed in 111 patients enrolled in five phase I and II clinical trials, where sorafenib 200 or 400 mg was administered twice daily as a single agent or in combination therapy. All patients were genotyped for polymorphisms in metabolic enzymes for sorafenib. Population PK analysis was performed by using nonlinear mixed effects modelling (NONMEM). The final model was validated using visual predictive checks and nonparametric bootstrap analysis.
A one compartment model with four transit absorption compartments and enterohepatic circulation (EHC) adequately described sorafenib disposition. Baseline bodyweight was a statistically significant covariate for distributional volume, accounting for 4% of inter-individual variability (IIV). PK model parameter estimates (range) for an 80 kg patient were clearance 8.13 l h(-1) (3.6-22.3 l h(-1) ), volume 213 l (50-1000 l), mean absorption transit time 1.98 h (0.5-13 h), fraction undergoing EHC 50% and average time to gall bladder emptying 6.13 h.
Overall, population PK analysis was consistent with known biopharmaceutical/PK characteristics of oral sorafenib. No clinically important PK covariates were identified.
索拉非尼是一种多激酶抑制剂，对 B-raf、C-raf、VEGFR2、PDGFRβ 和 FGFR1 具有活性。索拉非尼已在临床上获准用于治疗肾细胞癌（RCC）和肝细胞癌（HCC）。索拉非尼的药代动力学（PK）在个体之间差异很大。索拉非尼的暴露量增加与剂量不成比例（可能是由于溶解度有限）。索拉非尼经历肠肝循环（EHC）。
这是第一项使用基于索拉非尼已知处置特征（如延迟/溶解度限制的胃肠道吸收和 EHC）的模型来描述索拉非尼 PK 的研究。EHC 模型的参数化使用方波函数来描述胆囊排空。本研究评估了基线体重、BSA、年龄、性别、肝功能参数、肾功能参数以及 CYP3A41B、CYP3A53C、UGT1A93 和 UGT1A95 对索拉非尼 PK 的影响。未发现有临床意义的混杂因素。该模型可用于模拟和探索替代给药方案，并开发索拉非尼的暴露-反应关系。
描述固体肿瘤患者中索拉非尼的药代动力学（PK），并评估人口统计学、临床和药代遗传学（CYP3A41B、CYP3A53C、UGT1A93 和 UGT1A95）混杂因素对索拉非尼处置的可能影响。
在五项 I 期和 II 期临床试验中，对 111 名患者进行了 PK 评估，其中 200 或 400 mg 索拉非尼每天两次作为单药或联合治疗给药。所有患者均进行了代谢酶多态性的基因分型。采用非线性混合效应模型（NONMEM）进行群体 PK 分析。使用可视化预测检查和非参数自举分析验证最终模型。
一个具有四个转运吸收室和肠肝循环（EHC）的单室模型能够很好地描述索拉非尼的分布。基线体重是分布容积的一个具有统计学意义的混杂因素，占个体间变异的 4%（4%）。80 公斤患者的 PK 模型参数估计值（范围）为清除率 8.13 l/h（3.6-22.3 l/h），容积 213 l（50-1000 l），平均吸收转运时间 1.98 h（0.5-13 h），经历 EHC 的分数为 50%，胆囊排空的平均时间为 6.13 h。
总体而言，群体 PK 分析与口服索拉非尼的已知生物制药/PK 特征一致。未发现有临床意义的 PK 混杂因素。
